Semisynthetic Amides of Polyene Antibiotic Natamycin

Natamycin is a macrolide polyene antibiotic, characterized by a potent broad spectrum antifungal activity and low toxicity. However, it is not used for the treatment of systemic mycoses due to its low bioavailability and low solubility in aqueous solutions. In order to create new semisynthetic antifungal agents for treatment of mycoses, a series of water-soluble amides of natamycin were synthesized. Antifungal activities of natamycin derivatives were investigated against Candida spp., including a panel of Candida auris clinical isolates and filamentous fungi. Toxicity for mammalian cells was assayed by monitoring antiproliferative activity against human postnatal fibroblasts (HPF) and human embryonic kidney cells (HEK293). By comparing leakage of contents from ergosterol versus cholesterol containing vesicles, a ratio that characterizes the efficacy and safety of natamycin and its derivatives was determined (EI, efficiency index). Ability of all tested semisynthetic natamycines to prevent proliferation of the yeast Candida spp. cells was comparable or even slightly higher to those of parent antibiotic. Interestingly, amide 8 was more potent than natamycin (1) against all tested C. auris strains (MIC values 2 μg/mL vs 8 μg/mL, respectively). Among 7 derivatives, amide 10 with long lipophilic side chains showed the highest EI and strong antifungal activity in vitro but was more toxic against HPF. In vivo experiments with amide 8 showed in vivo efficacy on a mouse candidemia model with a larger LD50/ED50 ratio in comparison to amphotericin B. © 2022 American Chemical Society.

Авторы
Tevyashova A.N. , Efimova S.S. , Alexandrov A.I. , Ghazy E.S. , Bychkova E.N. , Solovieva S.E. , Zatonsky G.B. , Grammatikova N.E. , Dezhenkova L.G. , Pereverzeva E.R. , Isakova E.B. , Ostroumova O.S. , Omelchuk O.A. , Muravieva V.V. , Krotova M.M. , Priputnevich T.V. , Shchekotikhin A.E.
Издательство
American Chemical Society
Номер выпуска
1
Язык
Английский
Страницы
42-55
Статус
Опубликовано
Том
9
Год
2023
Организации
  • 1 Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow, 119021, Russian Federation
  • 2 Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky Avenue, St. Petersburg, 194064, Russian Federation
  • 3 Federal Research Center Fundamentals of Biotechnology, the Russian Academy of Sciences, Bach Institute of Biochemistry, 33 Leninsky Avenue, Bld. 2, Moscow, 119071, Russian Federation
  • 4 Institute of Biochemical Technology and Nanotechnology, Peoples’ Friendship University of Russia (RUDN), 6 Miklukho-Maklaya Street, Moscow, 117198, Russian Federation
  • 5 Department of Microbiology, Faculty of Pharmacy, Tanta University, Tanta, 31111, Egypt
  • 6 National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparin Street, Moscow, 117997, Russian Federation
Ключевые слова
amides; antifungal activity; calcein leakage; Natamycin; polyene antibiotics; semisynthetic derivatives; unilamellar vesicles; water-solubility
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Ryazantsev S.V., Sivoplyasova S.Yu.
Социологические исследования. Russian Academy of Sciences. Том 2023. 2023. С. 158-160